Surgery has been the most successful treatment for morbid obesity. The main objective of this grant proposal is to determine why lower gut signals generated in bypass surgery have been so successful in causing reduced food intake and body weight loss. We recently discovered that lower gut signals also cause a 10-25 percent increase in energy expenditure. One objective of this grant proposal is to determine how stimulation of different lengths of the ileum, caecum and colon affect energy balance and the plasma levels of the lower gut hormones: neurotensin; PYY and GLP1. Another objective is to determine the role of the extrinsic nerves to the ileum in altering food intake, energy expenditure and body weight by doing ileal transplantation surgery or denervation of the superior mesenteric nerves. A time course of the changes in energy expenditure, upper gut tissue growth and plasma lower gut hormone levels resulting from ileal transposition will be investigated in preparation for a later peptide infusion study. The role of the various macronutrients in changing energy balance and lowering body weight will be assessed by feeding various diets to rats with a 20 cm segment of ileum moved up to the mid-duodenum. The short-term objective of this research is to understand the internal control of daily intake and energy expenditure. The long-term objective is to find a medical treatment (drug or hormone analog) for obesity. In Western societies, obesity is a major medical problem that causes a great deal of human suffering. Obesity is associated with such chronic and debilitating conditions as diabetes, cancer (breast, endometrial, prostate and colon), hypertension, hyperlipidemia, stroke and heart disease. An effective medical treatment for obesity would improve the quality of life for millions of people and would reduce the cost of long-term health care.